PROJECT SUMMARY Low back pain is the leading cause of disability, and is closely linked to disc degeneration. Poor disc nutrition is a key factor involved in degeneration onset and progression, and is a major obstacle that could hinder the success of biologic therapies. The premise of this new project is that low cartilage endplate (CEP) permeability limits disc nutrient supply and cell function, and that we can identify patients with adequate nutrient supply who might benefit from biologic therapy through non-invasive assessment of CEP permeability. We propose innovative studies in cells, tissues, and human subjects that will: 1) identify critical values of CEP permeability needed for nutrient and metabolite transport under static and dynamic loads; 2) discover compositional and microstructural characteristics that hinder solute transport; 3) validate MRI techniques that are sensitive to these characteristics; and 4) determine the clinical relevance of low CEP permeability in human subjects. Three complementary aims are proposed. In Aim 1 we will develop a quantitative relationship between CEP permeability, cell density, and disc cell function using a novel in vitro diffusion chamber. By incubating the chambers with cadaveric CEP samples with a wide range of permeabilities, we will establish critical values of CEP permeability necessary to sustain cell densities associated with healthy discs. We will also quantify how dynamic loads enhance solute transport across the CEP and discover the range of CEP permeabilities and solute sizes where transport enhancement is greatest. In Aim 2 we will determine the relationship between solute transport and various measures of CEP biochemical composition, matrix porosity, and organization. This knowledge will provide a mechanistic link between CEP composition and disc health. In Aim 3 we will test the clinical relevance of low CEP permeability in human subjects using a combination of new MRI techniques that are sensitive to CEP permeability and disc cell metabolic stress. We will also compare the relative contributions of low CEP permeability vs. poor vascularity. The results from these studies will address an unmet clinical need and exert a broad impact by: 1) providing validated tools and a mechanistic framework to determine the role of CEP permeability in disc degeneration severity; 2) establishing the first non-invasive selection criteria to identify discs that can support the higher nutrient demands required by biologic therapies; and 3) guiding development of new treatments that improve disc health by enhancing CEP permeability.